New study of stem cell therapy in ischemic stroke

New study from our Stem Cell Research Group at Bei­jing Neu­ro­sur­gi­cal Insti­tute pro­vides deeper under­stand­ing of ther­a­peu­tic mech­a­nisms of stem cell ther­apy for stroke in a rat model. This study is published in the August issue of the Jour­nal of Trans­la­tional Med­i­cine.

Back­ground

Ischemic stroke is a com­mon neu­ro­log­i­cal dis­or­der and is one of the lead­ing causes of casu­alty world­wide. Cur­rent treat­ments are pri­mar­ily pal­lia­tive and are use­ful to only a minor­ity of patients after stroke. Cur­rently, there is no effec­tive treat­ment for restor­ing the neu­ro­log­i­cal func­tions lost dur­ing a stroke.

The abil­ity of neural stem cells (NSC) to dif­fer­en­ti­ate into neural cells has been seen in cul­ture. Given the com­plex­ity of both the struc­ture and func­tion of the cen­tral ner­vous sys­tem (CNS), it is crit­i­cal to under­stand the mech­a­nisms by which trans­planted neural cells can replace the dam­aged cells and inter­act with healthy host cells in a well-organized manner.

Cell-based ther­apy might elicit a chap­er­one effect in the at-risk neural tis­sue sur­round­ing the lesioned area via the up-regulation of neu­rotrophic and neu­ro­pro­tec­tive fac­tors, which help to pro­mote the sur­vival, migra­tion and dif­fer­en­ti­a­tion of endoge­nous pre­cur­sors after stroke.

The rela­tion­ship between func­tional improve­ments in ischemic rats given a neural stem cell (NSC) trans­plant and the mod­u­la­tion of the class I major his­to­com­pat­i­bil­ity com­plex (MHC) medi­ated by NSC-derived neu­rotrophins was inves­ti­gated, the authors write as back­ground infor­ma­tion in the article.

Results

We found a sig­nif­i­cant increase of nerve growth fac­tor (NGF), brain-derived neu­rotropic fac­tor (BDNF) and eurotrophin-3 (NT-3) tran­scripts and nerve growth fac­tor (NGF) pro­teins in both the neural stem cell (NSC) cul­tures and the cere­bral spinal fluid (CSF) of the rats. The immuno­chem­i­cal stain­ing for major his­to­com­pat­i­bil­ity com­plex (MHC) in brain sec­tions and the enzyme-linked immunosor­bent assay of CSF were carried out in sham-operated rats and rats with sur­gi­cally induced focal cere­bral ischemia. These groups were fur­ther divided into ani­mals that did and did not receive NGF admin­is­tra­tion or NSC trans­plant into the cis­terna magna. Our results show an up-regulation of class I MHC in the ischemic rats with NGF and NSC admin­is­tra­tion. The extent of caspase-III immunore­ac­tiv­ity was com­pa­ra­ble among three arms in the ischemic rats.

Motor func­tion

Motor function – ischemic rats with either NGF injection or neural stem cell transplant.

Analy­ses of motor func­tion over four weeks of sham-operated nor­mal con­trol rats, ischemic con­trol rats and ischemic rats with either NGF injec­tion or neural stem cell transplant. This suggests that NSC trans­plant and NGF admin­is­tra­tion could enhance symp­to­matic relief.

His­tol­ogy

Immuno­his­to­chem­i­cal stain­ing of MHC. Reddish-brown immunore­ac­tiv­ity of class I and II MHC were shown in panel A and B, respectively. A rep­re­sen­ta­tive coro­nal sec­tion of the hip­pocam­pus of an ischemic rat brain without injec­tion of NGF or NSC exhib­ited no pos­i­tiv­ity of class I MHC (A-i). Intense stain­ing of class I MHC was noted in the cyto­plasm of pyra­mi­dal neu­rons in the hip­pocam­pus of ischemic rats under­gone neural stem cell trans­plant for four weeks (A-ii). Clus­ters of cells with class I MHC-positivity were evi­dent in the infarcted brain parenchyma of trans­planted rats (A-iii and A-iv). A com­pa­ra­ble extent of class II MHC was noted in ischemic rats irre­spec­tive of any ther­apy but unre­mark­able in nor­mal rat (panel B, top row). Reddish-brown stain­ing of Class II MHC was evi­dent in the infarcted brain parenchyma (B-i), along the meninge (B-ii), areas near the ven­tric­u­lar lin­ing and vas­cu­lar wall near the hip­pocam­pus (B-iv) of trans­planted rats. Scale bars: 75 μm

Con­clu­sions

The find­ings pre­sented here pro­vide fur­ther insights into the mech­a­nisms of neural stem cells in the regen­er­a­tion of the cen­tral ner­vous sys­tem. Should the MHC mod­u­la­tion medi­ated by NSC-derived neu­rotrophins be elu­ci­dated, strate­gic cel­lu­lar ther­apy for neural injuries and neuro-degenerative dis­eases may be rev­o­lu­tion­ized, and novel treat­ment modal­i­ties could be developed.

This study was sup­ported in part by the grant ref­er­ence 30371452 of the National Nat­ural Sci­ence Foun­da­tion of China.